FDA Study Finds No Link Between Ziagen and Heart Attacks

A US Food and Drug Administration (FDA) analysis of
26 trials comparing Ziagen (abacavir) to other drugs
found no evidence that this antiretroviral raises the
risk of myocardial infarction (heart attack).1 Ziagen is
part of the two-drug combination Epzicom or Kivexa
and the three-drug combination Trizivir.

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Earlier, a large study of people taking antiretrovirals2
and analysis of SMART trial results3 suggested that Ziagen
does raise the risk of heart attack and other heart
disease. But the FDA study contradicts that finding. For
people with HIV and physicians unsure about how to
interpret all these findings, the FDA offers some advice,
summarized below in What the results mean for you.

The DAD Study Group analyzed the impact of current
or recent nucleosides in 33,347 people taking antiretrovirals.2 Using standard statistical methods, the DAD
researchers found no associations between the heart
attack rate and total or recent use of Retrovir (zidovudine),
Zerit (stavudine), or Epivir (lamivudine). But in an
analysis that accounted for 10-year risk of heart disease,
recent use of Ziagen raised the heart attack risk 89%, and
recent use of Videx (didanosine) raised the risk 49%.

The SMART trial randomized HIV-positive people to
take antiretrovirals continuously or to interrupt treatment
according to their CD4 count. Analysis of heart disease
rates in these people determined that recent Ziagen
use almost doubled the risk of major heart disease (heart
attack, stroke, or surgery for coronary artery disease).3

Partly because of the DAD and SMART results, experts
who write antiretroviral guidelines in the United States
removed Ziagen from the list of drugs recommended
for a first antiretroviral combination. But several other
studies found no link between Ziagen and heart disease.
And safety data collected by Ziagen's maker saw no hint
that Ziagen makes heart disease more likely. The FDA
decided the issue is important enough to examine in a
different way -- by comparing heart attack rates in people
who took Ziagen in randomized trials with rates in people
who did not take Ziagen in those trials.

How the study worked. FDA researchers reviewed
four databases to find randomized trials (that is, trials in
which study participants are assigned by chance to one
treatment or another). The trials selected for analysis
had to meet five requirements: (1) patients were adults,
(2) at least 50 people were studied, (3) the trial was completed,
(4) the trial was not planned mainly to measure
antiretroviral levels in people, and (5) the trial did not
take place in Africa.

The FDA team used standard statistical methods to determine
whether heart attack rates differed in people
taking antiretroviral combinations including Ziagen versus
people taking combinations not including Ziagen.

What the study found. The FDA found 26 trials to
analyze. Sixteen trials were conducted by GlaxoSmith-
Kline, the company that makes Ziagen. Five trials were
run by the US AIDS Clinical Trials Group (ACTG). And
five trials were run by physicians at university medical
centers. Together, the studies included 5028 people taking
Ziagen and 4840 taking combinations not including
Ziagen. Average follow-up (patient monitoring time) in
these studies was 719 person-years, or an average 1.6
years for each person. The FDA relied on heart attack
reports noted by the original researchers; they did not
analyze these findings further to confirm that all these
people had heart attacks.

About 80% of people in these trials were men, and their
ages averaged about 40 years. CD4 counts when trials
began averaged 360 in the GlaxoSmithKline trials, 236
in the ACTG trials, and 252 in the university trials. The
FDA rated overall heart attack risk in these people as
"moderate" (0.45%).

The main analysis found no difference in heart attack
rate between people taking Ziagen and people not taking
Ziagen in these studies. When the FDA team looked
only at trials run by Ziagen's maker, they also found no
difference in heart attack rate with and without Ziagen.
The same was true for the ACTG trials and the university
trials. No single trial analyzed had evidence that Ziagen
raises the risk of heart attack. The FDA performed
further analyses to determine the statistical power of
their study to detect a heart attack difference between
people taking versus not taking Ziagen. Note 4 in the
References summarizes these technical details.

What the results mean for you. The FDA researchers
concluded that their findings "raise significant
uncertainty about the likelihood of [a Ziagen-heart
attack] association."

It is important to understand that the FDA study analyzed
trials that were not planned to figure the risk of
heart attack or any heart disease in people taking Ziagen
or non-Ziagen combinations. One of two earlier studies
that did find a higher heart attack risk with Ziagen is a
cohort study.2 In this type of study, researchers monitor
many health changes in antiretroviral-treated people
over time, but those people are not randomly assigned
to take one set of antiretrovirals or another. As a result,
it is possible that factors not included in the analysis may
explain why a higher proportion of people taking Ziagen
had heart attacks.

An advantage of this kind of cohort study is that it includes
a much larger number of people than an analysis
of randomized trials. There were 33,347 people in the
DAD cohort study and 157,912 person-years of observation.2 In contrast, there were 9868 people in the FDA
study and an average of 719 person-years of observation
in each of the 26 trials analyzed.1 Also, average age in
the FDA study was 40 compared with 49 in the cohort
study, which means people in the FDA study would be
less likely to have heart attacks because they were younger.
However, statistical analysis by the FDA researchers
convinced them that their results make it highly unlikely
that Ziagen raises the heart attack risk in these 26 trials.4
In a statement about this study, the FDA said "healthcare
professionals should continue to prescribe [Ziagen]
according to the professional label. Patients should not
stop taking their [Ziagen] without first talking to their
healthcare professional."5 The FDA also advised people
with HIV to discuss any questions or concerns about Ziagen
with their physician.

As people with HIV grow older thanks to effective antiretroviral
therapy, heart attacks and other heart disease
pose a growing threat. The two preceding articles in this
issue of HIV Treatment Alerts! review studies that identify
factors that raise the risk of heart disease in people with
HIV. It is important to realize that several recent studies,
including the original SMART trial,6 found that antiretroviral
therapy lowers the risk of heart disease when all
antiretrovirals are considered together. Interrupting antiretroviral
therapy in the SMART trial raised the risk of
major heart disease. Fear of heart disease is certainly not
a reason to stop antiretroviral therapy or to delay starting.
However, many people with HIV have heart attack
risk factors that can be avoided or changed (see box).

"Based on our [statistical] simulations, the power of our study to exclude a relative risk of 1.8 with the observed myocardial
infarction background risk (0.45%) was 0.62; however, lack of power does not explain the observed risk difference of 0.008%
with a 95% confidence interval of (-0.26%, 0.27%). The simulation to assess the power demonstrates that our study had a probability
of 0.95 to find a risk difference greater than 0.1%. Our study's finding is very unlikely if the true risk of [Ziagen] is 1.8 or
higher at the observed background myocardial infarction risk (0.45%)."

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